In addition to their role in hemostasis, platelets are also immune modulators. They can promote either pro- or anti-inflammatory responses through diverse mechanisms based on the individual immunological milieu21–24. Platelets are involved in the pathogenesis of various autoimmune diseases25–27. Our findings in this study are important because they emphasize the fact that platelet activation plays a pivotal role in disease aggravation, which involves abnormal immunity similar to that observed in other autoimmune diseases. The expression of CD62P in platelets was upregulated in patients with UC, which is consistent with the findings in previous studies28,29. Herein, we demonstrate that this upregulation is correlated with the severity of mucosal inflammation. CD62P, a member of the selectin family, is a 140 kDa membrane glycoprotein located in the α-granules and dense granules of platelets and endothelial cells. Upon platelet activation, the α-granule membrane fuses with the platelet plasma membrane, leading to upregulation of CD62P on the platelet surface30. In contrast, the expression levels of CD40L, CD63, PAC1, annexin V, and CD36 did not differ between the HC and UC groups. These data suggest that the kinetics of CD62P is different from those of other platelet activation markers in patients with UC, which might be relevant to the understanding of disease pathophysiology and aid in identifying new therapeutic targets. Disease progression may increase the number of factors that result in the exposure of CD62P on platelets. For instance, platelets can be activated by shear stress on the wall of blood vessels, which is induced by endothelial dysfunction during chronic inflammation31. Notably, biochemicals, such as adenosine diphosphate (ADP), arachidonic acid, thrombin receptor activating peptide 6, and thrombin, rather than shear stress contribute to the exposure of CD62P on platelets32. ADP is released from various cell populations, such as apoptotic cells, activated immune cells, necrotic cells, and activated platelets, in the inflammatory milieu. Although ADP plays a role in tissue repair and hemostasis, it is also involved in inflammatory responses and thrombosis33. Arachidonic acid is released from cell membranes and mediates wound healing and inflammatory responses34,35. Thrombin, a serine protease synthesized in the liver, plays a role in hemostasis and promotes platelet aggregation in inflamed colon mucosa36. Taken together, we speculate that mucosal injuries trigger further activation of the immune system and mucosal healing, leading to the upregulation of CD62P on platelets by biochemicals rather than CD62P being constitutively active in UC. In contrast to CD62P expression, the concentration of the soluble form of CD62P decreased as mucosal damage progressed. A tendency for downregulation of sCD62P with disease progression has also been observed in gastric cancer; the expression of sCD62P was lower in stage III and IV patients than in stage I and II patients37. Because sCD62P is shed from platelet membranes, elevated sCD62P levels in mucosal remission might reflect reduced CD62P expression on the platelet membranes in patients with UC.
The contact between platelets and monocytes is mediated by adhesion via CD62P on platelets and PSGL1 on monocytes, which leads to the formation of PMCs and activation of monocytes11,12,38. Because platelet activation is a primary factor in the aggregation of platelets and monocytes, PMCs are a sensitive indicator of platelet activation. There are conflicting reports that PMC kinetics is positively or inversely correlated with disease severity in UC39,40. In the present study, the highest proportion of PMCs was observed in patients with MES3. The expression of CD16 was higher in monocytes that were conjugated with platelets than in the unconjugated ones. Moreover, the proportion of PMCs in patients with mucosal remission after treatment was significantly reduced, but CD62P and sCD62P levels were not altered. Taken together, our findings indicate that PMCs, promoted by platelet activation via CD62P upregulation in the inflammatory milieu, sensitively reflect mucosal healing; however, platelets are latently activated within a short period after mucosal remission. Therefore, maintenance therapy after mucosal remission is reasonable based on CD62P kinetics.
This study had some limitations. We did not assess the role of PMCs in the pathogenesis of UC. Whether PMCs accelerate or inhibit inflammatory responses remains controversial41,42. Further studies are needed to clarify this issue. Interestingly, patients with severe COVID-19 show platelet activation and PMC formation, which correlate with poor prognosis43.
Modulation of CD62P expression in platelets may be a potential target for therapeutic interventions aimed at preventing inappropriate platelet activation and controlling excessive clotting in UC. Crizanlizumab is a monoclonal antibody against human CD62P that has been approved for the treatment of vaso-occlusive crisis in Sickle cell disease44. A phase 2 study on the efficacy of crizanlizumab in sickle cell disease revealed no serious adverse effects, including bleeding events45. However, considering their pharmacological action, it is not confirmed whether CD62P antibodies are usable for patients with an underlying risk of intestinal bleeding, and this must be rigorously evaluated.
In summary, CD62P is upregulated in patients with UC. We show that CD62P expression is positively and sCD62P levels are negatively correlated with mucosal inflammation. Notably, PMCs, which express CD16, also correlate with mucosal injury. The CD62P–PMCs axis may be explored for understanding the UC pathogenesis and for the development of new therapeutics against this intractable disease.